Highlights from Recent Cancer Literature
Journal: Cancer Research (2012)

Vivanco I, Robbins HI, Rohle D, Campos C, Grommes C, Nghiemphu PL, et al. Differential sensitivity of glioma- versus lung cancer–specific EGFR mutations to EGFR kinase inhibitors. Cancer Discov 2012;2:458–71.Barkovich KJ, Hariono S, Garske AL, Zhang J, Blair JA, Fan Q-W, et al. Kinetics of inhibitor cycling underlie therapeutic disparities between EGFR-driven lung and brain cancers. Cancer Discov 2012;2:450–57.Mutational activation of kinases in cancer often shows dramatic effects to targeted therapy. An exception to this rule, however, is the role of some mutationally activated alleles of the epidermal growth factor receptor (EGFR). Although EGFR is mutationally activated in both lung and brain cancers, only patients with lung cancer show a clear response to therapy. The brain cancer glioblastoma multiforme (GBM) often shows amplification of EGFR, with amplified tumors typically expressing a deletion in the ligand-binding domain of EGFR, associated with constitutive activation. A subset of patients with non–small cell lung cancer also shows mutational activation of EGFR through mutations in the kinase domain. Two recent articles analyze the differences in response rates in lung and brain cancer patients to inhibitors of EGFR. Vivanco and colleagues demonstrate that so-called type I inhibitors (e.g., erlotinib and CI-1033), which bind EGFR when in the active state, were most effective in lung cancer–type mutations, whereas type II inhibitors (e.g., lapatinib and HKI-272), which bind to EGFR in an active state, show preferential activity against brain cancer–derived mutations. Barkovich and colleagues have complemented this story by measuring the degree to which type I inhibitors occupied the ATP-binding sites of brain cancer– and lung cancer–derived alleles, when expressed independently in glioma- or rodent fibroblast–derived cell lines. At similar levels of kinase site occupancy, type I inhibitors induced a great degree of proliferative arrest in lung cancer–derived mutants when compared with brain cancer–derived mutants of EGFR. The basis for this difference was traced in part to rapid rates of inhibitor binding and release in brain cancer mutants, as compared with lung cancer mutations. Collectively, these articles argue that EGFR is a viable target in brain cancer, with the caveat that very efficient inhibition is required to achieve a cellular response. As demonstrated by Vivanco and colleagues, the levels of inhibition required (even using the type II inhibitor lapatanib in patients with brain cancer) are higher than those that are readily achievable in patients. These studies further illuminate the complexities and challenges of targeting EGFR in patients with cancer and offer insights toward improving the outcome for patients with EGFR-driven cancers.Gorovets D, Kannan K, Shen R, Kastenhuber ER, Islamdoust N, Campos C, et al. IDH mutation and neuroglial developmental features define clinically distinct subclasses of lower-grade diffuse astrocytic glioma. Clin Cancer Res 2012; 18:2490–501.Although a substantive effort has been made in the classification of glioblastoma [World Health Organization (WHO) grade IV glioma], less is known about molecular classification of lower-grade (WHO grade II–III) gliomas. A wide range of clinical outcomes exists in patients with low-grade astrocytic gliomas. To better understand the basis for this variation in outcomes, a group from Memorial Sloan-Kettering Cancer Center screened 101 astrocytic grade II and III astrocytic glioma samples for mutations in IDH1 and IDH2. Consistent with prior findings, 69% harbored mutations in IDH1, and patients with IDH-mutant tumors were on average younger than patients with IDH wild-type tumors. Additional profiling and data from immunohistochemistry revealed that IDH-mutant subsets were enriched for mutations in TP53 and for expression of platelet-derived growth factor receptor A (PDGFRA). In contrast, the IDH wild-type subset displayed activated phosphoinositide 3 kinase (PI3K)/AKT signaling based on elevated levels of phospho-PRAS40, genomic loss of the PTEN locus, and amplification of epidermal growth factor receptor (EGFR). Gene expression profiling revealed 3 subgroups: neuroblastic (NB), early progenitor-like (EPL), and pre-glioblastoma (PG). NB-signature genes mapped extensively to molecular networks with mature neuronal biology, and EPL-signature genes were enriched in developmental pathways, such as BMP signaling and WNT signaling. PG-signature genes showed functional associations with glioblastoma, whereas IDH wild-type tumors were predominantly in the PG subclass. EPL and NB subclasses, both with IDH-mutant tumors, differed in the frequency of TP53 mutation and PDGFRA expression (both more common in the EPL subclass). With respect to DNA copy number aberrations, the PG tumors showed a GBM-like signature (loss of 10q and amplification of EGFR). EPL tumors featured broad gains of 8q, a region that includes MYC, along with losses of 13q, 19q, and 9p23. Finally, NB tumor copy number profiles were relatively silent, with only 8q gain noted as a recurring aberration. Consistent with the genomic profiles, patients with PG tumors had a significantly worse outcome than those with NB and EPL tumors. Further, molecular subclass designations were more predictive of survival than WHO grades were in multivariate analyses. Overall, the authors define a molecular framework with which to understand lower-grade gliomas and in doing so have identified a subgroup very similar to glioblastoma as well as 2 IDH-mutant subclasses. Further analyses, such as the ongoing effort by the Cancer Genome Atlas to profile grade II and III gliomas, should allow further refinement and validation of this important work.Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 2012;21:418–29.Pancreatic ductal adenocarcinomas (PDAC) are among the most lethal human cancers: 5 years after diagnosis, less than 5% of patients with PDAC are still alive. Provenzano and colleagues suggest both a reason for this poor prognosis and a way of improving treatment. In human PDAC and in a mouse genetic model of the disease, a dense infiltrate of fibroblasts, immune cells, and endothelial cells surrounds the malignant cells. This desmoplastic reaction leads to an interstitial fluid pressure almost 10-fold higher than that in the normal pancreas. High interstitial pressure stops perfusion, diffusion, and convection of small-molecule drugs and collapses the vasculature, making the PDAC tumor microenvironment a drug-free sanctuary. The authors found in both human and mouse PDAC that the major constituent of the tumor extracellular matrix was the glycosoaminoglycan, hyaluronic acid. They gave tumor-bearing mice an enzymatic drug called PEGPH20 that was able to dissolve hyaluronic acid, normalize interstitial fluid pressure, expand the tumor vasculature, and increase the efficacy of gemcitabine chemotherapy. Mouse survival was almost doubled. Two concerns were that ablating hyaluronic acid would affect normal tissues or increase metastases by increasing blood flow to the primary tumor. Neither of these possibilities was observed. In fact, metastases were strongly reduced, suggesting that hyaluronic acid was required in metastatic niches. Treatment with an enzymatic agent in an adjuvant setting may prevent or delay the appearance of pancreatic metastases and increase the efficacy of chemotherapy or targeted drugs.Heering J, Weis N, Holeiter M, Neugart F, Staebler A, Fehm TN, et al. Loss of ceramide transfer protein augments epidermal growth factor receptor signaling in breast cancer. Cancer Res; Published OnlineFirst April 3, 2012; doi:10.1158/0008-5472.CAN-11-3069.Triple-negative breast cancer (TNBC) is a heterogeneous tumor that is difficult to manage therapeutically due to the lack of expression of estrogen receptors, progesterone receptors, and HER2. In this context, an understanding of the underlying molecular genetic pathway is crucial for the development of strategies for effective disease management. Heering and colleagues have examined the expression pattern of ceramide transfer protein (CERT) and its cross-talk with the epidermal growth factor receptor (EGFR) signaling pathway in triple-negative breast cancer. CERT is responsible for transferring ceramide from the endoplasmic reticulum to the Golgi complex for conversion into sphingomyelin, which, in combination with cholesterol, constitutes the highly orchestrated lipid raft in the cell membrane. CERT expression was found to be reduced significantly in triple-negative breast cancer tissues. Remarkably, knockdown of CERT augmented epidermal growth factor (EGF)–induced EGFR/Akt activation, cellular motility, and focal adhesion clustering. CERT depletion also resulted in the alteration of lipid composition and physical properties of the plasma membrane. Moreover, the authors show that increased EGF signaling in CERT knockdown cells was mediated by phospholipase D, a master regulator of the ligand-inducible signaling of EGFR. Together, these data demonstrate a potential tumor-suppressive role for CERT and its involvement in key pathways leading to progression of breast cancer.Menon S, Yecies JL, Zhang HH, Howell JJ, Nicholatos J, Harputlugil E, et al. Chronic activation of mTOR complex 1 is sufficient to cause hepatocellular carcinoma in mice. Sci Signal 2012;5:ra24.A growing body of evidence links diet to increased cancer susceptibility. However, precise mechanisms by which metabolic dysregulation may lead to tumor formation are largely unknown. In this study, Menon and colleagues establish a novel mouse model of hepatocellular carcinoma (HCC) that arises as a result of chronic activation of the mTOR complex 1 pathway, a key cellular nutrient-sensing pathway. The authors show that mice harboring a liver-specific deletion of Tsc1, a key negative regulator of the mTORC1 pathway, recapitulate features of HCC that are observed in humans, including liver damage, inflammation, necrosis, and regeneration. The authors show that treatment with rapamycin blocks the pathologic features of HCC in this mouse model, illustrating that chronic mTORC1 activation is required for HCC development. They further show that loss of Tsc1 in the liver promoted hyperactive mTORC1 signaling, resulting in unresolved endoplasmic reticulum stress and defects in autophagy, leading to liver damage, which precedes HCC development. Therefore, this article provides a causal and mechanistic link between a nutrient-sensing pathway dysregulated by environmental factors such as obesity and tumor development. Furthermore, this mouse model for sporadic and heterogeneous HCC will be useful for dissecting molecular and genetic events that promote various stages of liver disease observed during the malignant progression.Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.